American Journal of Medical Genetics 435315-822 (1992)
Neurofibromatosis 1 and Osseous Fibrous Dysplasia in a Family Helena M. Schotland, Roswell Eldridge, Steve S . Sommer, and Martin Malawar Department of Medicine, New York University Medical Center, New York, New York (H.M.S.); Clinical Neurogenetic Studies, NEB, NINDS, National Institutes of Health, Bethesda, Maryland (R.E.); Department of Biochemistry and Molecular Biology, Mayo CliniclFoundation, Rochester, Minnesota (S.S.S.); OrthopediclOncology Surgery, Children's Hospital National Medical Center, George Washington University Medical Center, Washington, D.C. (M.M.) We report on the cosegregation of neurofibromatosis 1 (NF 1) and osseous fibrous dysplasia in a family. The father and3 children by 2 women are affected. A fourth child had neither NF 1 nor osseous fibrous dysplasia. All 4 affectedindividualshad NF 1, i.e., cafeau-lait spots in 4, neurofibromata in 4, Lisch nodules in 3, macrocrania in 3, scoliosis in 2, and curvature of the long bones in 2. Each demonstrated various fibroosseous lesions of the skeletonincludingnon-ossifyingfibromas in 3 and both non-ossifying fibromas and fibrous dysplasia in one. This pattern suggests that the fibrous bony lesions are a component of NF 1 in this family. Alternatively, a mutant gene resulting in the fibrous changes in bone could be linked to the gene for NF 1. Another possibility is the coincidence of the 2 non-linkedtraits segregating in the same family. Q 1992 Wiley-Liss, hc.
KEY WORDS fibrous dysplasia, neurofibromatosis 1, NF 1, non-ossifying fibroma, osseous fibrous dysplasia, pleiotropy, segregation INTRODUCTION We describe the occurrence in 4 relatives of two rare conditions. The first, neurofibromatosis 1 (NF 11, is a pleiotropic condition with autosomal dominant transmission. It is often associated with a variety of skeletal anomalies [Bahlin, 1978; Holt, 1978; Hunt and Pugh, 1961; Klatte et al., 19761. The second condition, osseous fibrous dysplasia, refers to benign dysplastic bone formation in combination with a fibrous stroma. It includes several specific subtypes such as fibrous dysplasia, nonFhceived for publication May 2,1991; revision received October 25, 1991. Address reprint requests to Helena M. Schotland, M.D., Department of Medicine, New York Veterans Administration Medical Center, 423 East 23rd Street, New York, NY 10010.
0 1992 Wiley-Liss, Inc.
ossifying fibroma, and an aggressive form of osseous fibrous dysplasia (Table I). The occurrence of osseous fibrous dysplasia is reported to be sporadic. There have been a t least 8 reports of NF 1and osseous fibrous dysplasia in individuals [Beggs et al., 1981; Erlemann et al., 1987; Faure et al., 1986; Goodnough et al., 1975; Gross et al., 1989;Mandell et al., 1979;Rosenberg et al., 1967; Schwartz and Ramos, 19801.However, a familial association has not been reported. We describe a father and 3 of his living children who have NF 1 and osseous fibrous dysplasia.
CLINICAL REPORTS We examined all the patients at the National Institutes of Health Interinstitute Genetics Clinic. Clinical and radiologic data are summarized in Table 11. Family pedigree is shown in Figure 1. Patient 1: T.D. Pedigree 111-26 The index case, T.D., weighed 3.72 kg at birth. Multiple cafe-au-lait spots were noted at birth. Motor and intellectual development were delayed. He walked 6 months after his peers and he did not use complete sentences until age 4. He did poorly in school, but completed 11 grades. Puberty began at age 13 years. At 18 years, he enlisted in the Navy and passed a standard Navy physical examination. T.D. soon began to notice a dull ache in his left leg. It was non-radiating and there was no obvious difference in the temperature of the legs. He received a medical discharge from the Navy 8 months after enlistment. On radiologic exam, severe bilateral osseous fibrous dysplasia of the knees was noted. Multiple cafe-au-lait spots and subcutaneous nodules were noted, and the diagnosis of NF 1was made. Physical examination: height of 164, (4th centile), weight of 64 kg (60th centile), and a OFC of 57 cm (70th centile). Cafe-au-lait spots, axillary freckling, neurofibromata, and Lisch nodules were present on examination. He was otherwise normal except for tenderness of the left knee. Radiographic evaluation included a complete skeletal survey and bone scintigraphy. Plain radiographs demonstrated bilateral, symmetrical lytic lesions of the distal femora and proximal tibiae (Fig. 2). The femoral
816
Schotland et al. TABLE I. Characteristics of Osseous Fibrous Dssplasia* Radiographic appearance __
Natural history
Subtype
Age of onset
Location
Histology
Genetics
Non-ossifying fibroma
Childhood
Appendicular Metaphyseal
Small, eccentric lesions with scalloped borders
Fibrous Some giant cells Evidence of phagocytosis No bone formation
Spontaneous healing with skeletal maturity
Fibrous dysplasia
Childhood Adolescence
Flat bones Pelvis Knees Metaphyseal
Central, “ground glass” appearance
Recurrence
Osseous fibrous dysplasia (aggressive type)
Childhood
Appendicular Metaphyseal Diaphyseal
Central, lytic, destructive
Fibrous “Fake trabeculae” (bone with no osteoblasts) Direct metaplasia Immature bone Active fibrous stroma Bone production (may have osteoblasts) Immature bone
Regressive Recurrence
Evans and Park report one family with 3 affected members-2 sibs and 1 offspring No families reportedsporadic occurrence
No families reportedsporadic occurrence
* [Bahlin, 1978; Evans and Park, 1978; Jaffe, 1958; Lichtenstein, 19721. TABLE 11. Summary of Clinical and Radiographic Data in 5 Cases Skin changes Case __-
SedAge
Caf6-aulait spots
Skeletal changes
Lisch Macrocrania nodules Neurofibromata (percentile)
T.D. Mi19 propositus
+
+
+
A.R. half-sib
Fi36
+
-
+
M.R. half-sib
W14
J.R. half-sib H.R. father
1
+
+
Mi12
-
-
-
Mi42
+
+
+
6
7
+
-
+ (>95%)
+
Scoliosis
(70%)
+
(>99%) -
Fibrous dysplasia
Curvature of tibia/ fibula
+
-
-
-
Bilateral distal fibulae, proximal tibiae and fibulae
+
+
+
+
-
-
-
-
-
+
-
T-L scoliosis (7 degrees) T-C scoliosis ( 5 degrees)
+
Non-ossifying fibromas
10
Fig. 1. Pedigree.
11
-
+
Bilateral fibulae
(>97%)
9
+
Bilateral fibulae
13
NF 1 and Osseous Fibrous Dysplasia
817
Fig. 2 . Bilateral, symmetrical lesions of the distal femurs and proximal tibias of Patient 1.
lesions were metaphyseal with well-defined margins, sclerotic borders, and some cortical thinning. The left proximal tibia (symptomatic) lesion involved the entire metaphysis and epiphyseal portion, with “ballooning”of the cortex, and destruction ofthe subchondral bone. The contralateral tibia showed similar findings but with less destruction. The radiographic appearance suggested a benign process. No other radiographic abnormalities were noted. Bone scintigraphy showed increased uptake corresponding to the plain radiographs. The bony defects of the left limb were treated in one stage by curettage and autogenous bone graft. At surgery, he had a large cystic cavity in the left tibia consisting of bloody fluid with an attenuated cortex and erosion of the adjacent subchondral bone. There was a thin fibrous lining of the cavity. Frozen section demonstrated benign fibrous tissue with multinucleated giant cells. This defect was reconstructed by segmental ipsilateral fibula bone grafts after thorough curettage. The distal femoral lesion was treated by curettage without bone grafts. Post-operatively, the left limb was immobilized in a long-leg cast for 9 months until radiographs demonstrated graft incorporation. A long-leg brace was utilized for an additional 3 months. Sections from the left femur curretings showed a lesion composed of spindle cells in interlacing bundles interspersed with giant cells. There were no neural The diagnosis was a non-ossifying fibroma (Fig. 3). A subcutaneous nodule was also examined histo-
Fig. 3. A non-ossifying fibroma taken from the left femur curettings of Patient 1.The lesion is composed of spindle cells in interlacing bundles interspersed with giant cells. There are no neural elements.
818
Schotland et al.
logically. It showed a nerve trunk which had become fect in the parietal region. Bone scintigraphy showed markedly widened with Schwann cells and bundles of increased uptake corresponding to the plain radiofibrous tissue in a loose stroma. The diagnosis was plexi- graphs. The forehead nodule was biopsied, and microscopic form neurofibroma (Fig. 4). examination showed compactly arranged fusiform and Patient 2: A.R. Pedigree 111-28 oval cells within a fibrocollagenous matrix. Several A.R. is the 16-year-oldhalf-sister of the index case. At large nerve branches were present within the tissue age one, a biopsy proven subcutaneous neurofibroma mass, and focal areas exhibited a plexiform pattern (Fig. was noted on her forehead. The nodule recurred as a 6). The diagnosis was neurofibroma. disfiguring midline lesion despite several surgical proPatient 3: M.R. Pedigree 111-29 cedures. Otherwise, she was in good health. M.R. is the 14-year-oldbrother of the previous patient Physical examination: height of 168 cm (85th centile), weight of 49.9 kg (15th centile), and a OFC of 58 cm and the half-brother of the index case. There were no (>95th centile). A 3 x 5 cm, firm, biopsy proven neuro- complaints and past medical history was unremarkable. Physical examination: height of 151 cm (12th centile), fibroma extended from the forehead down to the bridge of the nose and the left upper eyelid. Three neuro- weight of 41.1 kg (5th centile), and a OFC of 59 cm fibromata, multiple cafe-au-lait spots, and axillary (>99th centile). Multiple cafe-au-lait spots, a 2 x 4 cm freckling were present. Examination with a slit lamp neurofibroma, axillary freckling, and Lisch nodules did not show any Lisch nodules. Otherwise, she was were noted on examination. Findings on the remainder of the exam were within normal limits. normal on exam. Plain radiographs demonstrated an oval radiolucent Plain radiographs showed a lobulated lesion in the distal shaft of the right femur, which is well circum- defect in the distal metaphysis of the left femur (Fig. 7) scribed by osteosclerotic margins. The lesion originates and increased cortical bone thickening in the distal from the inner aspect of the bony cortex and bulges shaft of the right fibula. There is deformity in the within the cancellous bone and the medullary cavity of distal metaphysis of the right fibula. There is also a the distal femur. A similar, but smaller, lesion is seen in deformity in the trabecular pattern of the distal metathe distal metaphysis of the same femur (Fig. 5). Mini- physis of the right tibia. The fibulae are markedly mal scoliosis was seen in the thoraco-lumbar region. A bowed (Fig. 8). There is minimal scoliosis in the cerlateral view of the skull showed a radiolucent bony de- vico-thoracic region.
Fig. 4. A plexiform neurofibroma from Patient 1.The nerve trunk is markedly widened with Schwann cells and bundles offibrous tissue in a loose stroma.
Fig. 5. A lobulated lesion in the distal shaft of the right femur and a similar, but smaller lesion in the distal metaphysis ofthe same femur of Patient 2.
NF 1 and Osseous Fibrous Dysplasia
819
Fig, 7. An oval-shaped radiolucent defect in the distal metaphysis of the left distal femur in Patient 3.
Fig. 6. A neurofibroma from Patient 2. Compactly arranged fusiform and oval cells are seen within a fibrocollagenousmatrix. Several large nerve branches are present within the tissue mass and focal areas exhibit a plexiform pattern.
Patient 4: J.R. Pedigree 111-30 J.R. is the 12-year-oldbrother of the previous patient. There were no complaints and past history was unremarkable. Physical examination was unremarkable. No cafe-aulait spots were detected under either room light or Woods’ light. No neurofibromata, Lisch nodules, axillary freckling, or skeletal anomalies were seen. Radiographs of the upper and lower limbs were unremarkable. Patient 5: H.R. Pedigree 11-10 H.R. is the 42-year-old father of the previous 4 patients. He first noted neurofibromata on his abdomen at age 9 years. The number and size of his neurofibromata increased over time. At age 26, a large neurofibroma was removed from his right thigh. At age 37, six neurofibromata were removed from his face, neck, and abdoFig, 8. The fibulae are markedly bowed in Patient 3. men due to pain or change in size. Physical examination: height of 168 cm (15th centile), weight of 73 kg, and a OFC of 61 cm (>97th centile). Multiple cafe-au-lait spots, axillary freckling, greater than 100 neurofibromata, and 30-40 Lisch nodules Family History (Pedigree-Fig. 1) were noted on exam. Otherwise, he was normal. An infant son (111-27) of H.R. died at 3 months of Plain radiographs demonstrated focal areas of increased density in the distal left femur and proximal sudden infant death. Family history failed to show any evidence of NF 1or osseous fibrous dysplasia in H.R.’s right tibia (Fig. 9). The fibulae are bowed.
820
Schotland et al. TABLE 111. Reports of Neurofibromatosis 1 With Non-Ossifying Fibromas or F i b r o u s Dvsdasia ~
Authorlyear Rosenberg et al. 1967
Patient(s1 1 Familymother and 9 siblings
Diagnosis Propositus-fibrous dysplasia
Motherneurofibromatosis 1 8 Siblingsneurofibromatosis 1
Goodnough et al. 1975
1
Mandell et al. 1979
38
Schwartz and Ramos 1980
1
Neurofibromatosis 1 with incidental non-ossifying fibroma Neurofibromatosis 1
Neurofibromatosis 1 and multiple nonossifying fibromas
Bone changes
Skin changes
Fibrous dysplasia involving frontal bone and the floor of the anterior fossa. The roof of the right orbit was partially obscured and the proximal mandibular rami had an abnormal granular texture Scoliosis, irregular trabecular pattern of the mandible and granular lesions in the mandibular rami Sibling 2-retarded ossification of anterior fontanel and a defect in the metopic suture Siblings 4,5,6-cortical defects in the femur Non-ossifying fibroma in the right distal femur
At least 6 cafe-au-lait spots > 1.5 cm
9 patients with bone changes-5 had multiple fibrocystic lesions, 4 had characteristic osseous lesions around the knees; vertebral scalloping and pedicle abnormalities were seen Non-ossifying fibromas around knees and ankles, endosteal sclerosis of right femur, dysplastic thickening of the diaphysis, lumbar scoliosis, and hypoplasia of the right iliac crest
All 9 of the patients with bone changes had 8 or more cafe-aulait spots and neurofibromata
Comments
~~
___
Multiple neurofibromata and at least 6 cafe-aulait spots > 1.5 cm 8 Siblings-at least 6 cafe-au-lait spots > 1.5 cm
Neurofibroma and multiple cafe-au-lait spots
Plexiform neurofibromas
(continued)
parents, 10 sibs, and the 35 nephews and nieces with whom he had contact. This strongly suggests that H.R. represents a new mutation t h a t arose in the germ line of his 32-year-old nonconsanguineous parents.
Fig. 9. Focal areas of increased density in the distal left femur and proximal right tibia of Patient 5.
DISCUSSION To our knowledge, there have been no previous reports of NF 1 with osseous fibrous dysplasia occurring in multiple family members. Jaffe remarked that a patient with lesions of disseminated non-ossifying fibroma and patches of brownish skin pigmentation, but without neurofibromata, could be interpreted as a n instance of neurofibromatosis dominated by bone lesions-an abortive form, or forme fruste, of neurofibromatosis [Jaffe, 19581. Since that time, a number of individuals have been reported with both NF 1and osseous fibrous dysplasia (Table 111). Faure et al. reported the occurrence of NF 1 with non-ossifying fibromas in 4 patients, 2 of whom were sisters [Faure et al., 19861. This is not a n obvious case of N F 1in Patient 4.She initially presented with a left suprarenal neuroblastoma with bone metastases. She later developed growth hormone insuffi-
NF 1 and Osseous Fibrous Dysplasia
821
TABLE 111. (continued) Authorlyear Beggs et al. 1981
Faure et al. 1985
Erlemann et al.
Diaenosis
Bone changes
Skin changes
Neurofibromatosis 1 non-ossifying fibroma, and coarctation of the aortic arch
Multiple lesions at the ends of the shafts of the distal femorae, tibiae, and fibulae (non-ossifying fibromas)
Multiple cafe-au-lait spots and neurofibromata
Patient 1
Neurofibromatosis 1 and non-ossifying fibroma
Numerous cafe-au-lait spots and 2 neurofibromas
Patient 2
Neurofibromatosis I and “fibrous bone defects”
Patient 3
Neurofibromatosis 1 and non-ossifying fibroma
Patient 4 (sister of Patient 3)
Non-ossifying fibroma
Large non-ossifying fibromas of both femurs and the left tibia Severe scoliosis; congenital pseudarthrosis of the right forearm, numerous fibrous defects of bone including the right clavicle, humerus, radius, both fibulae, and the right upper tibial metaphysis Large non-ossifying fibromas of upper tibial and fibular metaphyses Non-ossifying fibromas of both femurs tibiae, fibulae, and right humerus
Patient(s1 1
4
3
1987
Gross et al. 1989
Schotland et al.
Comments _______
1
1 Family
Neurofibromatosis 1 and non-ossifying fibroma Neurofibromatosis 1 and non-ossifying fibroma
Neurofibromatosis 1 and osseous fibrous dysplasia
Multiple osteolytic lesions with sclerotic margins Multiple lytic lesions in the distal aspect of both femurs and proximal portion of the right tibia, “ribbon rib” deformity of the right 10th-12th ribs, hypoplasia of the pedicles of the 12th thoracic and 1st lumbar vertebrae Multiple lesions a t the ends of the shafts of the distal femorae and in the tibiae and fibulae, bowing of the fibulae, mild scoliosis, macrocrania
ciency, precocious puberty, and non-ossifying fibromas. In fact, the patient’s findings have some overlap with Albright syndrome [Riccardi, 19871. Goodnough et al. (1975) thought that the relationship of non-ossifying fibromas to neurofibromatosis was coincidental. Mandell et al. [1979] however, thought that when multiple fibrocystic lesions are present around the knee, the diagnosis of neurofibromatosis should be considered and a biopsy is unnecessary. Schwartz and Ramos [ 19801 called non-ossifying fibromas another phenotypic mani-
Multiple caf6-au-lait spots
Multiple cafe-au-lait spots None
Patient initially presented with a left suprarenal neuroblastoma with bone metastases. She also had growth hormone insufficiency and precocious puberty. This does not clearly represent an instance of neurofibromatosis in this patient.
Multiple cafe-au-lait spots, axillary freckling, bilateral Lisch nodules
Multiple cafe-au-lait spots, neurofibromata, axillary freckling, Lisch modules
festation of the mesodermal abnormalities in neurofibromatosis. Rosenberg et al. [1967] and Campanacci et al. [1983] also proposed that there may be a relationship between the 2 diseases. There is a striking parallel between N F 1 and JaffeCampanacci syndrome [Mirra et al., 1982; Campanacci et al., 19831.This syndrome is characterized by cafe-aulait spots and multiple non-ossifying fibromas and is often associated with mental retardation. It differs from N F 1in that, to our knowledge, neurofibromata have not
822
Schotland et al.
been described in patients with Jaffe-Campanacci syndrome, and in addition, a heritable basis has not been established. Jaffe’s description above of a patient with disseminated non-ossifying fibromas and patches of brownish skin pigmentation has been cited as the first description of Jaffe-Campanacci syndrome. Molecular studies first showed the locus of the NF 1 gene on chromosome 17 [Barker et al., 1987;Seizinger et al., 19871 and more recently, the gene has been cloned [Cawthon et al., 1990;Viskochil et al., 19901.It would be of interest to perform molecular studies on this family to determine if the association of NF 1and osseous fibrous dysplasia represents: (1)a particular mutation in the NF 1 gene with an atypical clinical phenotype, (2) a deletion or rearrangement which disrupts the NF 1gene and a neighboring gene whose defect results in osseous fibrous dysplasia, (3) a mutation in a novel gene whose defect results in both disease, and (4) coincidence, although highly unlikely, is another possibility.
Erlemann R, Fischedick AR, Edel G, Peters PE, Galanski M (1987): Neurofibromatosis and multiple nonossifying bone fibromas. Fortschr Rontgenstr 147:20-24. Evans GA, Park WM (1978): Familial multiple non-osteogenic fibromata. J . Bone Joint Surg. 60 B:416-419. Faure C, Laurent JM, Schmit P, Sirinelli 0 (1986): Multiple and large non-ossifying fibromas in children with neurofibromatosis. Ann Radiol (Paris) 29:369-373. Goodnough CP, Kuhlmann RP, Stark E (1975):Von Recklinghausen’s neurofibromatosis with nonosteogenic fibroma. New York State Journal of Medicine 75:2407-2409. Gross ML, Soberman N, Dorfman HD, Seimon LP: Case report 556 (1989): Multiple non-ossifying fibromas of long bones in a patient with neurofibromatosis. Skeletal Radiol 18:389-391. Holt JF (1978): Neurofibromatosis in children. AJR 130:615-639. Hunt JC, Pugh DG (1961): Skeletal lesions in neurofibromatosis. Radiology 76:l-23. Jaffe HL (1958): “Tumors and Tumorous Conditions of the Bones and Joints.” Philadelphia: Lea and Feibiger. Klatte EC, Franken EA, Smith JA (1976):The radiographic spectrum in neurofibromatosis. Semin Roentgen01 11:17-33. Lichtenstein L (1972): “Bone Tumors” 4th Ed. St. Louis: C.V. Mosby. Mandell GA, Dalinka MR, Boleman BG (1979): Fibrous lesions in the REFERENCES lower extremities in neurofibromatosis. AJR 133:1135-1138. Bahlin DC (1978): “Bone Tumors: General Aspects and Data on 6221 Mirra JM, Gold RH, Rand F (1982): Disseminated nonossifying Cases.” 3rd Ed. Springfield: Charles C. Thomas. fibromas in association with cafe-au-lait spots (Jaffe-Campanacci Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D, Bishop syndrome). Clin Orthop 168:192-205. DT, Carey J , Baty B, Kivlin J , Willard H, Waye JS, Greig G, Riccardi VM (1987):Neurofibromatosis and Albright’s syndrome. DerLeinwand L, Nakamura Y, OConnell P, Leppert M, Lalouel JM, matologic Clinics 5: 193-203. White R, Skolnick M (1987): Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Rosenberg RN, Sassin J, Zimmerman EA, Carter S (1967): The interrelationship of neurofibromatosis and fibrous dysplasia. Arch Neur Science 236:1100-1 102. 17:174-179. Beggs I, Shaw DG, Brenton DP, Fisher C (1981): An unusual case of neurofibromatosis: Cystic bone lesions and coarctation of the aortic Schwartz AM, Ramos RM (1980): Neurofibromatosis and multiple nonossifying fibromas. AJR 135:617-619. arch. Brit. J . Radiol. 54:416-418. Campanacci M, Laus M, Boriani S (1983): Multiple non-ossifying Seizinger BR et al. (1987): Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell fibromata with extraskeletal anomalies: a new syndrome? J Bone 49:589-594. Joint Surg (Br) 65-B:627-632. Cawthon RM, Weiss R, Xu G, Viskochil D, Culver M, Stevens J , Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J , Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O’ConRobertson M, Dunn D, Gesteland R, OConnell P, White R (1990): A nell P (1990): Deletions and a translocation interrupt a cloned gene major segment of the neurofibromatosis type 1 gene: cDNA seat the neurofibromatosis type 1locus. Cell 62:187-192. quence, genomic structure, and point mutations. Cell 62:193-201.
Neurofibromatosis 1 and Osseous Fibrous Dysplasia in a Family Helena M. Schotland, Roswell Eldridge, Steve S . Sommer, and Martin Malawar Department of Medicine, New York University Medical Center, New York, New York (H.M.S.); Clinical Neurogenetic Studies, NEB, NINDS, National Institutes of Health, Bethesda, Maryland (R.E.); Department of Biochemistry and Molecular Biology, Mayo CliniclFoundation, Rochester, Minnesota (S.S.S.); OrthopediclOncology Surgery, Children's Hospital National Medical Center, George Washington University Medical Center, Washington, D.C. (M.M.) We report on the cosegregation of neurofibromatosis 1 (NF 1) and osseous fibrous dysplasia in a family. The father and3 children by 2 women are affected. A fourth child had neither NF 1 nor osseous fibrous dysplasia. All 4 affectedindividualshad NF 1, i.e., cafeau-lait spots in 4, neurofibromata in 4, Lisch nodules in 3, macrocrania in 3, scoliosis in 2, and curvature of the long bones in 2. Each demonstrated various fibroosseous lesions of the skeletonincludingnon-ossifyingfibromas in 3 and both non-ossifying fibromas and fibrous dysplasia in one. This pattern suggests that the fibrous bony lesions are a component of NF 1 in this family. Alternatively, a mutant gene resulting in the fibrous changes in bone could be linked to the gene for NF 1. Another possibility is the coincidence of the 2 non-linkedtraits segregating in the same family. Q 1992 Wiley-Liss, hc.
KEY WORDS fibrous dysplasia, neurofibromatosis 1, NF 1, non-ossifying fibroma, osseous fibrous dysplasia, pleiotropy, segregation INTRODUCTION We describe the occurrence in 4 relatives of two rare conditions. The first, neurofibromatosis 1 (NF 11, is a pleiotropic condition with autosomal dominant transmission. It is often associated with a variety of skeletal anomalies [Bahlin, 1978; Holt, 1978; Hunt and Pugh, 1961; Klatte et al., 19761. The second condition, osseous fibrous dysplasia, refers to benign dysplastic bone formation in combination with a fibrous stroma. It includes several specific subtypes such as fibrous dysplasia, nonFhceived for publication May 2,1991; revision received October 25, 1991. Address reprint requests to Helena M. Schotland, M.D., Department of Medicine, New York Veterans Administration Medical Center, 423 East 23rd Street, New York, NY 10010.
0 1992 Wiley-Liss, Inc.
ossifying fibroma, and an aggressive form of osseous fibrous dysplasia (Table I). The occurrence of osseous fibrous dysplasia is reported to be sporadic. There have been a t least 8 reports of NF 1and osseous fibrous dysplasia in individuals [Beggs et al., 1981; Erlemann et al., 1987; Faure et al., 1986; Goodnough et al., 1975; Gross et al., 1989;Mandell et al., 1979;Rosenberg et al., 1967; Schwartz and Ramos, 19801.However, a familial association has not been reported. We describe a father and 3 of his living children who have NF 1 and osseous fibrous dysplasia.
CLINICAL REPORTS We examined all the patients at the National Institutes of Health Interinstitute Genetics Clinic. Clinical and radiologic data are summarized in Table 11. Family pedigree is shown in Figure 1. Patient 1: T.D. Pedigree 111-26 The index case, T.D., weighed 3.72 kg at birth. Multiple cafe-au-lait spots were noted at birth. Motor and intellectual development were delayed. He walked 6 months after his peers and he did not use complete sentences until age 4. He did poorly in school, but completed 11 grades. Puberty began at age 13 years. At 18 years, he enlisted in the Navy and passed a standard Navy physical examination. T.D. soon began to notice a dull ache in his left leg. It was non-radiating and there was no obvious difference in the temperature of the legs. He received a medical discharge from the Navy 8 months after enlistment. On radiologic exam, severe bilateral osseous fibrous dysplasia of the knees was noted. Multiple cafe-au-lait spots and subcutaneous nodules were noted, and the diagnosis of NF 1was made. Physical examination: height of 164, (4th centile), weight of 64 kg (60th centile), and a OFC of 57 cm (70th centile). Cafe-au-lait spots, axillary freckling, neurofibromata, and Lisch nodules were present on examination. He was otherwise normal except for tenderness of the left knee. Radiographic evaluation included a complete skeletal survey and bone scintigraphy. Plain radiographs demonstrated bilateral, symmetrical lytic lesions of the distal femora and proximal tibiae (Fig. 2). The femoral
816
Schotland et al. TABLE I. Characteristics of Osseous Fibrous Dssplasia* Radiographic appearance __
Natural history
Subtype
Age of onset
Location
Histology
Genetics
Non-ossifying fibroma
Childhood
Appendicular Metaphyseal
Small, eccentric lesions with scalloped borders
Fibrous Some giant cells Evidence of phagocytosis No bone formation
Spontaneous healing with skeletal maturity
Fibrous dysplasia
Childhood Adolescence
Flat bones Pelvis Knees Metaphyseal
Central, “ground glass” appearance
Recurrence
Osseous fibrous dysplasia (aggressive type)
Childhood
Appendicular Metaphyseal Diaphyseal
Central, lytic, destructive
Fibrous “Fake trabeculae” (bone with no osteoblasts) Direct metaplasia Immature bone Active fibrous stroma Bone production (may have osteoblasts) Immature bone
Regressive Recurrence
Evans and Park report one family with 3 affected members-2 sibs and 1 offspring No families reportedsporadic occurrence
No families reportedsporadic occurrence
* [Bahlin, 1978; Evans and Park, 1978; Jaffe, 1958; Lichtenstein, 19721. TABLE 11. Summary of Clinical and Radiographic Data in 5 Cases Skin changes Case __-
SedAge
Caf6-aulait spots
Skeletal changes
Lisch Macrocrania nodules Neurofibromata (percentile)
T.D. Mi19 propositus
+
+
+
A.R. half-sib
Fi36
+
-
+
M.R. half-sib
W14
J.R. half-sib H.R. father
1
+
+
Mi12
-
-
-
Mi42
+
+
+
6
7
+
-
+ (>95%)
+
Scoliosis
(70%)
+
(>99%) -
Fibrous dysplasia
Curvature of tibia/ fibula
+
-
-
-
Bilateral distal fibulae, proximal tibiae and fibulae
+
+
+
+
-
-
-
-
-
+
-
T-L scoliosis (7 degrees) T-C scoliosis ( 5 degrees)
+
Non-ossifying fibromas
10
Fig. 1. Pedigree.
11
-
+
Bilateral fibulae
(>97%)
9
+
Bilateral fibulae
13
NF 1 and Osseous Fibrous Dysplasia
817
Fig. 2 . Bilateral, symmetrical lesions of the distal femurs and proximal tibias of Patient 1.
lesions were metaphyseal with well-defined margins, sclerotic borders, and some cortical thinning. The left proximal tibia (symptomatic) lesion involved the entire metaphysis and epiphyseal portion, with “ballooning”of the cortex, and destruction ofthe subchondral bone. The contralateral tibia showed similar findings but with less destruction. The radiographic appearance suggested a benign process. No other radiographic abnormalities were noted. Bone scintigraphy showed increased uptake corresponding to the plain radiographs. The bony defects of the left limb were treated in one stage by curettage and autogenous bone graft. At surgery, he had a large cystic cavity in the left tibia consisting of bloody fluid with an attenuated cortex and erosion of the adjacent subchondral bone. There was a thin fibrous lining of the cavity. Frozen section demonstrated benign fibrous tissue with multinucleated giant cells. This defect was reconstructed by segmental ipsilateral fibula bone grafts after thorough curettage. The distal femoral lesion was treated by curettage without bone grafts. Post-operatively, the left limb was immobilized in a long-leg cast for 9 months until radiographs demonstrated graft incorporation. A long-leg brace was utilized for an additional 3 months. Sections from the left femur curretings showed a lesion composed of spindle cells in interlacing bundles interspersed with giant cells. There were no neural The diagnosis was a non-ossifying fibroma (Fig. 3). A subcutaneous nodule was also examined histo-
Fig. 3. A non-ossifying fibroma taken from the left femur curettings of Patient 1.The lesion is composed of spindle cells in interlacing bundles interspersed with giant cells. There are no neural elements.
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logically. It showed a nerve trunk which had become fect in the parietal region. Bone scintigraphy showed markedly widened with Schwann cells and bundles of increased uptake corresponding to the plain radiofibrous tissue in a loose stroma. The diagnosis was plexi- graphs. The forehead nodule was biopsied, and microscopic form neurofibroma (Fig. 4). examination showed compactly arranged fusiform and Patient 2: A.R. Pedigree 111-28 oval cells within a fibrocollagenous matrix. Several A.R. is the 16-year-oldhalf-sister of the index case. At large nerve branches were present within the tissue age one, a biopsy proven subcutaneous neurofibroma mass, and focal areas exhibited a plexiform pattern (Fig. was noted on her forehead. The nodule recurred as a 6). The diagnosis was neurofibroma. disfiguring midline lesion despite several surgical proPatient 3: M.R. Pedigree 111-29 cedures. Otherwise, she was in good health. M.R. is the 14-year-oldbrother of the previous patient Physical examination: height of 168 cm (85th centile), weight of 49.9 kg (15th centile), and a OFC of 58 cm and the half-brother of the index case. There were no (>95th centile). A 3 x 5 cm, firm, biopsy proven neuro- complaints and past medical history was unremarkable. Physical examination: height of 151 cm (12th centile), fibroma extended from the forehead down to the bridge of the nose and the left upper eyelid. Three neuro- weight of 41.1 kg (5th centile), and a OFC of 59 cm fibromata, multiple cafe-au-lait spots, and axillary (>99th centile). Multiple cafe-au-lait spots, a 2 x 4 cm freckling were present. Examination with a slit lamp neurofibroma, axillary freckling, and Lisch nodules did not show any Lisch nodules. Otherwise, she was were noted on examination. Findings on the remainder of the exam were within normal limits. normal on exam. Plain radiographs demonstrated an oval radiolucent Plain radiographs showed a lobulated lesion in the distal shaft of the right femur, which is well circum- defect in the distal metaphysis of the left femur (Fig. 7) scribed by osteosclerotic margins. The lesion originates and increased cortical bone thickening in the distal from the inner aspect of the bony cortex and bulges shaft of the right fibula. There is deformity in the within the cancellous bone and the medullary cavity of distal metaphysis of the right fibula. There is also a the distal femur. A similar, but smaller, lesion is seen in deformity in the trabecular pattern of the distal metathe distal metaphysis of the same femur (Fig. 5). Mini- physis of the right tibia. The fibulae are markedly mal scoliosis was seen in the thoraco-lumbar region. A bowed (Fig. 8). There is minimal scoliosis in the cerlateral view of the skull showed a radiolucent bony de- vico-thoracic region.
Fig. 4. A plexiform neurofibroma from Patient 1.The nerve trunk is markedly widened with Schwann cells and bundles offibrous tissue in a loose stroma.
Fig. 5. A lobulated lesion in the distal shaft of the right femur and a similar, but smaller lesion in the distal metaphysis ofthe same femur of Patient 2.
NF 1 and Osseous Fibrous Dysplasia
819
Fig, 7. An oval-shaped radiolucent defect in the distal metaphysis of the left distal femur in Patient 3.
Fig. 6. A neurofibroma from Patient 2. Compactly arranged fusiform and oval cells are seen within a fibrocollagenousmatrix. Several large nerve branches are present within the tissue mass and focal areas exhibit a plexiform pattern.
Patient 4: J.R. Pedigree 111-30 J.R. is the 12-year-oldbrother of the previous patient. There were no complaints and past history was unremarkable. Physical examination was unremarkable. No cafe-aulait spots were detected under either room light or Woods’ light. No neurofibromata, Lisch nodules, axillary freckling, or skeletal anomalies were seen. Radiographs of the upper and lower limbs were unremarkable. Patient 5: H.R. Pedigree 11-10 H.R. is the 42-year-old father of the previous 4 patients. He first noted neurofibromata on his abdomen at age 9 years. The number and size of his neurofibromata increased over time. At age 26, a large neurofibroma was removed from his right thigh. At age 37, six neurofibromata were removed from his face, neck, and abdoFig, 8. The fibulae are markedly bowed in Patient 3. men due to pain or change in size. Physical examination: height of 168 cm (15th centile), weight of 73 kg, and a OFC of 61 cm (>97th centile). Multiple cafe-au-lait spots, axillary freckling, greater than 100 neurofibromata, and 30-40 Lisch nodules Family History (Pedigree-Fig. 1) were noted on exam. Otherwise, he was normal. An infant son (111-27) of H.R. died at 3 months of Plain radiographs demonstrated focal areas of increased density in the distal left femur and proximal sudden infant death. Family history failed to show any evidence of NF 1or osseous fibrous dysplasia in H.R.’s right tibia (Fig. 9). The fibulae are bowed.
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Schotland et al. TABLE 111. Reports of Neurofibromatosis 1 With Non-Ossifying Fibromas or F i b r o u s Dvsdasia ~
Authorlyear Rosenberg et al. 1967
Patient(s1 1 Familymother and 9 siblings
Diagnosis Propositus-fibrous dysplasia
Motherneurofibromatosis 1 8 Siblingsneurofibromatosis 1
Goodnough et al. 1975
1
Mandell et al. 1979
38
Schwartz and Ramos 1980
1
Neurofibromatosis 1 with incidental non-ossifying fibroma Neurofibromatosis 1
Neurofibromatosis 1 and multiple nonossifying fibromas
Bone changes
Skin changes
Fibrous dysplasia involving frontal bone and the floor of the anterior fossa. The roof of the right orbit was partially obscured and the proximal mandibular rami had an abnormal granular texture Scoliosis, irregular trabecular pattern of the mandible and granular lesions in the mandibular rami Sibling 2-retarded ossification of anterior fontanel and a defect in the metopic suture Siblings 4,5,6-cortical defects in the femur Non-ossifying fibroma in the right distal femur
At least 6 cafe-au-lait spots > 1.5 cm
9 patients with bone changes-5 had multiple fibrocystic lesions, 4 had characteristic osseous lesions around the knees; vertebral scalloping and pedicle abnormalities were seen Non-ossifying fibromas around knees and ankles, endosteal sclerosis of right femur, dysplastic thickening of the diaphysis, lumbar scoliosis, and hypoplasia of the right iliac crest
All 9 of the patients with bone changes had 8 or more cafe-aulait spots and neurofibromata
Comments
~~
___
Multiple neurofibromata and at least 6 cafe-aulait spots > 1.5 cm 8 Siblings-at least 6 cafe-au-lait spots > 1.5 cm
Neurofibroma and multiple cafe-au-lait spots
Plexiform neurofibromas
(continued)
parents, 10 sibs, and the 35 nephews and nieces with whom he had contact. This strongly suggests that H.R. represents a new mutation t h a t arose in the germ line of his 32-year-old nonconsanguineous parents.
Fig. 9. Focal areas of increased density in the distal left femur and proximal right tibia of Patient 5.
DISCUSSION To our knowledge, there have been no previous reports of NF 1 with osseous fibrous dysplasia occurring in multiple family members. Jaffe remarked that a patient with lesions of disseminated non-ossifying fibroma and patches of brownish skin pigmentation, but without neurofibromata, could be interpreted as a n instance of neurofibromatosis dominated by bone lesions-an abortive form, or forme fruste, of neurofibromatosis [Jaffe, 19581. Since that time, a number of individuals have been reported with both NF 1and osseous fibrous dysplasia (Table 111). Faure et al. reported the occurrence of NF 1 with non-ossifying fibromas in 4 patients, 2 of whom were sisters [Faure et al., 19861. This is not a n obvious case of N F 1in Patient 4.She initially presented with a left suprarenal neuroblastoma with bone metastases. She later developed growth hormone insuffi-
NF 1 and Osseous Fibrous Dysplasia
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TABLE 111. (continued) Authorlyear Beggs et al. 1981
Faure et al. 1985
Erlemann et al.
Diaenosis
Bone changes
Skin changes
Neurofibromatosis 1 non-ossifying fibroma, and coarctation of the aortic arch
Multiple lesions at the ends of the shafts of the distal femorae, tibiae, and fibulae (non-ossifying fibromas)
Multiple cafe-au-lait spots and neurofibromata
Patient 1
Neurofibromatosis 1 and non-ossifying fibroma
Numerous cafe-au-lait spots and 2 neurofibromas
Patient 2
Neurofibromatosis I and “fibrous bone defects”
Patient 3
Neurofibromatosis 1 and non-ossifying fibroma
Patient 4 (sister of Patient 3)
Non-ossifying fibroma
Large non-ossifying fibromas of both femurs and the left tibia Severe scoliosis; congenital pseudarthrosis of the right forearm, numerous fibrous defects of bone including the right clavicle, humerus, radius, both fibulae, and the right upper tibial metaphysis Large non-ossifying fibromas of upper tibial and fibular metaphyses Non-ossifying fibromas of both femurs tibiae, fibulae, and right humerus
Patient(s1 1
4
3
1987
Gross et al. 1989
Schotland et al.
Comments _______
1
1 Family
Neurofibromatosis 1 and non-ossifying fibroma Neurofibromatosis 1 and non-ossifying fibroma
Neurofibromatosis 1 and osseous fibrous dysplasia
Multiple osteolytic lesions with sclerotic margins Multiple lytic lesions in the distal aspect of both femurs and proximal portion of the right tibia, “ribbon rib” deformity of the right 10th-12th ribs, hypoplasia of the pedicles of the 12th thoracic and 1st lumbar vertebrae Multiple lesions a t the ends of the shafts of the distal femorae and in the tibiae and fibulae, bowing of the fibulae, mild scoliosis, macrocrania
ciency, precocious puberty, and non-ossifying fibromas. In fact, the patient’s findings have some overlap with Albright syndrome [Riccardi, 19871. Goodnough et al. (1975) thought that the relationship of non-ossifying fibromas to neurofibromatosis was coincidental. Mandell et al. [1979] however, thought that when multiple fibrocystic lesions are present around the knee, the diagnosis of neurofibromatosis should be considered and a biopsy is unnecessary. Schwartz and Ramos [ 19801 called non-ossifying fibromas another phenotypic mani-
Multiple caf6-au-lait spots
Multiple cafe-au-lait spots None
Patient initially presented with a left suprarenal neuroblastoma with bone metastases. She also had growth hormone insufficiency and precocious puberty. This does not clearly represent an instance of neurofibromatosis in this patient.
Multiple cafe-au-lait spots, axillary freckling, bilateral Lisch nodules
Multiple cafe-au-lait spots, neurofibromata, axillary freckling, Lisch modules
festation of the mesodermal abnormalities in neurofibromatosis. Rosenberg et al. [1967] and Campanacci et al. [1983] also proposed that there may be a relationship between the 2 diseases. There is a striking parallel between N F 1 and JaffeCampanacci syndrome [Mirra et al., 1982; Campanacci et al., 19831.This syndrome is characterized by cafe-aulait spots and multiple non-ossifying fibromas and is often associated with mental retardation. It differs from N F 1in that, to our knowledge, neurofibromata have not
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been described in patients with Jaffe-Campanacci syndrome, and in addition, a heritable basis has not been established. Jaffe’s description above of a patient with disseminated non-ossifying fibromas and patches of brownish skin pigmentation has been cited as the first description of Jaffe-Campanacci syndrome. Molecular studies first showed the locus of the NF 1 gene on chromosome 17 [Barker et al., 1987;Seizinger et al., 19871 and more recently, the gene has been cloned [Cawthon et al., 1990;Viskochil et al., 19901.It would be of interest to perform molecular studies on this family to determine if the association of NF 1and osseous fibrous dysplasia represents: (1)a particular mutation in the NF 1 gene with an atypical clinical phenotype, (2) a deletion or rearrangement which disrupts the NF 1gene and a neighboring gene whose defect results in osseous fibrous dysplasia, (3) a mutation in a novel gene whose defect results in both disease, and (4) coincidence, although highly unlikely, is another possibility.
Erlemann R, Fischedick AR, Edel G, Peters PE, Galanski M (1987): Neurofibromatosis and multiple nonossifying bone fibromas. Fortschr Rontgenstr 147:20-24. Evans GA, Park WM (1978): Familial multiple non-osteogenic fibromata. J . Bone Joint Surg. 60 B:416-419. Faure C, Laurent JM, Schmit P, Sirinelli 0 (1986): Multiple and large non-ossifying fibromas in children with neurofibromatosis. Ann Radiol (Paris) 29:369-373. Goodnough CP, Kuhlmann RP, Stark E (1975):Von Recklinghausen’s neurofibromatosis with nonosteogenic fibroma. New York State Journal of Medicine 75:2407-2409. Gross ML, Soberman N, Dorfman HD, Seimon LP: Case report 556 (1989): Multiple non-ossifying fibromas of long bones in a patient with neurofibromatosis. Skeletal Radiol 18:389-391. Holt JF (1978): Neurofibromatosis in children. AJR 130:615-639. Hunt JC, Pugh DG (1961): Skeletal lesions in neurofibromatosis. Radiology 76:l-23. Jaffe HL (1958): “Tumors and Tumorous Conditions of the Bones and Joints.” Philadelphia: Lea and Feibiger. Klatte EC, Franken EA, Smith JA (1976):The radiographic spectrum in neurofibromatosis. Semin Roentgen01 11:17-33. Lichtenstein L (1972): “Bone Tumors” 4th Ed. St. Louis: C.V. Mosby. Mandell GA, Dalinka MR, Boleman BG (1979): Fibrous lesions in the REFERENCES lower extremities in neurofibromatosis. AJR 133:1135-1138. Bahlin DC (1978): “Bone Tumors: General Aspects and Data on 6221 Mirra JM, Gold RH, Rand F (1982): Disseminated nonossifying Cases.” 3rd Ed. Springfield: Charles C. Thomas. fibromas in association with cafe-au-lait spots (Jaffe-Campanacci Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D, Bishop syndrome). Clin Orthop 168:192-205. DT, Carey J , Baty B, Kivlin J , Willard H, Waye JS, Greig G, Riccardi VM (1987):Neurofibromatosis and Albright’s syndrome. DerLeinwand L, Nakamura Y, OConnell P, Leppert M, Lalouel JM, matologic Clinics 5: 193-203. White R, Skolnick M (1987): Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Rosenberg RN, Sassin J, Zimmerman EA, Carter S (1967): The interrelationship of neurofibromatosis and fibrous dysplasia. Arch Neur Science 236:1100-1 102. 17:174-179. Beggs I, Shaw DG, Brenton DP, Fisher C (1981): An unusual case of neurofibromatosis: Cystic bone lesions and coarctation of the aortic Schwartz AM, Ramos RM (1980): Neurofibromatosis and multiple nonossifying fibromas. AJR 135:617-619. arch. Brit. J . Radiol. 54:416-418. Campanacci M, Laus M, Boriani S (1983): Multiple non-ossifying Seizinger BR et al. (1987): Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell fibromata with extraskeletal anomalies: a new syndrome? J Bone 49:589-594. Joint Surg (Br) 65-B:627-632. Cawthon RM, Weiss R, Xu G, Viskochil D, Culver M, Stevens J , Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J , Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O’ConRobertson M, Dunn D, Gesteland R, OConnell P, White R (1990): A nell P (1990): Deletions and a translocation interrupt a cloned gene major segment of the neurofibromatosis type 1 gene: cDNA seat the neurofibromatosis type 1locus. Cell 62:187-192. quence, genomic structure, and point mutations. Cell 62:193-201.
